1. Field of the Invention
This invention relates to stable, biologically active analogues of thromboxane A.sub.2 useful as thrombotic agents.
2. Brief Description of the Prior Art
The prostaglandins were first discovered in the 1920's and have proven since then to be among the most ubiquitous pharmaceutically active compounds ever tested. Their use and the use of analogues and derivatives thereof, has been suggested in as wide a range of applications as fertility control, induction of labor, regulation of blood pressure, regulation of blood clotting, control of asthma, anticonvulsion, antidepressing action and many others. A new compound has recently been discovered (Nature 263, 663 (1976); Prostaglandins, vol. 12, 685 and 715 (1976); Chem. and Engineering News, Dec. 20, 1976) which belongs to the general family of prostaglandins. The compound has been named prostacyclin and its structure has been proven by synthesis (Johnson, et al, Prostaglandins, 12, 915 (1976); Corey et al, J. Amer. Chem. Soc., 99, 2006 (1977)) to be that of formula I. (The numbering system for prostacyclins is given for reference): ##STR2## Its generic name is 6,9.alpha.-oxido-11.alpha., 15.alpha.-dihydroxyprosta (Z) 5, E (13)-dienoic acid. Prostacyclin is the most potent inhibitor of blood platelet aggregation of all the prostaglandins discovered to date. It has also been shown that prostacyclin destroys platelet aggregates after they have formed and that it has, in addition, a powerful action as a dilator of blood vessels. A second compound, which acts in an exactly opposite way to prostacyclin, has also recently been discovered by Hamberg and coworkers (Proc. Nat. Acad. of Sciences. USA. 72, 2994 (1975)). This metabolite, named thromboxane A.sub.2 (TA.sub.2) and shown in formula II below has potent thrombotic and smooth muscle constricting properties: Both prostacyclin (I) and TA.sub.2 (II) are derived from a common intermediate called endoperoxide, which in turn is synthesized from arachidonic acid by the enzyme cyclooxygenase. Prostacyclin is rapidly decomposed to 6-ketoprostaglandin F.sub.1.alpha. (6-keto PGF.sub.1.alpha.) and TA.sub.2 is rapidly decomposed to thromboxane B.sub.2 (TB.sub.2), less active final products in both cases. Both prostacyclin and TA.sub.2 have very short half-lives under physiological conditions; that of prostacyclin being about 2 minutes and that of TA.sub.2 only a mere 30 seconds at pH 7.4 and 37.degree. C. The lability of TA.sub.2 is caused by presence of a sensitive bicyclic acetal system. The relationships between these metabolites, their precursors, products, and the enzymatic systems catalyzing their formations and decompositions, are summarized in Scheme I: ##STR3## It can be seen that prostacyclin (produced by vascular endothelium) and thromboxane A.sub.2 (produced by platelets) have opposite physiological effects and are very short lived. The balance between the levels of prostacyclin and thromboxane A.sub.2, appears to maintain a finely tuned equilibrium between blood platelet aggregation versus dissolution and arterial constriction versus dilation.
Other important physiological effects which are mediated by the opposite transient actions of prostacyclin and TA.sub.2 are the maintenance of the normal integrity of vessel walls, limitation of thrombus formation, assistance in the formation of hemostatic plugs by diminished prostacyclin formation, blood pressure regulation, control of inflammation, prevention of gastric ulceration and other similar effects. The pharmacological use of these metabolites however, is severely hindered by their short half-lives, especially so in the case of TA.sub.2. Externally provided TA.sub.2 will fail to reach its target tissues intact in high enough concentrations to cause any effects. Furthermore, the need to maintain the drug in a totally anhydrous condition also prevents its ready shipment, storage and testing for pharmacological applications. Therefore, if an analogue or derivative of TA.sub.2 can be found which is stable and shows biological effects on blood platelets and arteries, such analogue would have wide applications in pharmacology and the treatment of cardiovascular and related diseases. The use of such a stable analogue of TA.sub.2 can be used for patients with cardiovascular diseases, such as thrombosis, heart attack, or arteriosclerosis. It can be used in shock, such as hemorrhagic shock.
Although several stable bioactive prostacyclin analogues have been prepared (see e.g., Nicolaou et al, Angewandte Chemie, Int. Ed. (English) 17, 293 (1978) and references cited therein; also U.S. patent application Ser. No. 886,141, filed Mar. 13, 1978) there have been, prior to this invention, only few reports of stable TA.sub.2 analogues with biological activity.
Nicolaou et al, (Proceed. of Nat. Acad. Sci, USA, 76, 2566 (1979)) describe pinane thromboxane PTA.sub.2 (formula III): ##STR4## This compound is a stable, biologically active thromboxane A.sub.2 analogue which inhibits coronary artery contraction at normal and high concentrations. It functions as an antagonist of natural TA.sub.2. This compound (PTA.sub.2) as well as a variety of derivatives and analogues thereof are disclosed in copending U.S. application Ser. No. 19,932, filed Mar. 12, 1979 by K. C. Nicolaou and R. Magolda. The synthesis of PTA.sub.2 has also been disclosed by Ansell et al at the Fourth International Prostaglandin Meeting held in Washington, D.C., May 1979 (Abstracts of the Meeting, page 5). However, PTA.sub.2 is the only stable TA.sub.2 analogue reported to date. A need therefore continues to exist for other stable thromboxane A.sub.2 analogues which show biological activity and are useful in cardiovascular therapy.